一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析

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一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析

李建 , 吴奇 , Ernest Hung Yu Ng , Ben Willem J. Mol , 吴效科 , Chi Chiu Wang

工程（英文） ›› 2022, Vol. 16 ›› Issue (9) : 198 -209.

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工程（英文） ›› 2022, Vol. 16 ›› Issue (9) : 198 -209. DOI: 10.1016/j.eng.2021.07.009

一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析

李建 ^a^,^b^,^c ,
吴奇 ^d ,
Ernest Hung Yu Ng ^e ,
Ben Willem J. Mol ^f ,
吴效科 ^a^,^g ,
Chi Chiu Wang ^c^,^h^,ⁱ^,^j

作者信息 +

^a Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China

^b Department of Obstetrics and Gynecology, The Affiliated Hospital of Gui Zhou Medical University, Guiyang 550004, China

^c Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China

^d Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 30009, China

^e Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China

^f Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia

^g Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin 1500036, China

^h Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China

ⁱ School of Biomedical Sciences, The Chinese University of Hong Kong Hong Kong 999077, China

^j The Chinese University of Hong Kong–Sichuan University Joint Laboratory of Reproductive Medicine, Hong Kong 999077, China

收起

Effects of Medicines and Supplements on Spontaneous Pregnancy and Semen Parameters in Male Infertility: A Systematic Review Update and Network Meta-Analysis

Jian Li ^a^,^b^,^c ,
Qi Wu ^d ,
Ernest Hung Yu Ng ^e ,
Ben Willem J. Mol ^f ,
Xiao Ke Wu ^a^,^g ,
Chi Chiu Wang ^c^,^h^,ⁱ^,^j

Author information +

^a Department of Obstetrics and Gynecology, First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China

^b Department of Obstetrics and Gynecology, The Affiliated Hospital of Gui Zhou Medical University, Guiyang 550004, China

^c Department of Obstetrics and Gynaecology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong 999077, China

^d Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 30009, China

^e Department of Obstetrics and Gynaecology, Queen Mary Hospital, The University of Hong Kong, Hong Kong 999077, China

^f Department of Obstetrics and Gynaecology, Monash University, Clayton, VIC 3168, Australia

^g Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin 1500036, China

^h Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong 999077, China

ⁱ School of Biomedical Sciences, The Chinese University of Hong Kong Hong Kong 999077, China

^j The Chinese University of Hong Kong–Sichuan University Joint Laboratory of Reproductive Medicine, Hong Kong 999077, China

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文章历史 +

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摘要

本研究采用网状荟萃分析对药物和补充剂治疗特发性男性不育症的疗效进行比较，以获得最佳治疗方法。对Medline、EMBASE、OVID和CNKI等数据库中发表于1990年1月至2021年6月的文献进行检索，检索关键词包括'男性不育''药物疗法''补充/营养疗法'及其相关术语等。将研究药物[主要包括促卵泡激素（FSH）、雄激素、克罗米芬/他莫昔芬（SERM）]或补充剂[主要是锌、硒、维生素C/E、卡尼丁、辅酶Q₁₀（CoQ₁₀）或联合治疗]治疗特发性不育男性的随机对照试验（RCT）纳入meta分析。按PRISMA声明中的报告规范提取数据，并使用偏倚风险工具和适用于网状meta分析的GRADE系统评估证据质量。研究的主要结局是活产率和自然妊娠率（SPR），次要结局是精子参数（包括精子浓度、前向运动百分比和形态）和不良反应。65项RCT被纳入分析，共包括7541名精子参数异常但激素水平正常的育龄男性。36项研究报道SPR，但仅三项研究报道活产率。纳入研究的质量评价为中、高级。与安慰剂或未治疗相比，卡尼汀联合维生素治疗显著增加SPR（RR = 3.7, 95% CI为1.6 ~ 8.5），脂肪酸补充剂显著增加精子浓度（MD = 12.5 × 10⁶ mL^–1, 95% CI为3.1 × 10⁶ ~ 22.0 × 10⁶）。SERM联合辅酶Q₁₀显著提升前向活力精子（MD = 11.0%, 95% CI为0.1% ~ 21.9%）和正常形态精子（MD = 11.0%, 95% CI为4.6% ~ 17.4%）。对改善SPR和精子浓度的最佳治疗方案分别是卡尼汀联合维生素和脂肪酸补充剂，即便排除具有高偏倚风险的研究，结果仍保持一致。对于少弱精子症男性，与安慰剂或未治疗相比，FSH（RR = 4.9, 95% CI为1.1 ~ 21.3）显著增加SPR，而SERM联合激肽酶可显著增加精子浓度（MD = 16.5 × 10⁶ mL^–1, 95% CI为1.6 × 10⁶ ~ 31.4 × 10⁶)，SERM联合辅酶Q₁₀则显著改善前向活力精子（MD = 11.3%, 95% CI为7.3% ~ 15.4%）和正常形态精子（MD = 11.2%, 95% CI为 5.4% ~ 16.9%）。在不良反应方面，脂肪酸补充剂和己酮可可碱分别与口臭或味觉差（RR = 8.1, 95% CI为1.0 ~ 63.5）和呕吐（RR = 8.0, 95% CI为1.0 ~ 63.0）相关。综上所述，对于改善不育男性配偶活产率的最佳治疗方案仍然不清楚。对于所有不孕夫妇和男性少弱精症不孕夫妇，卡尼汀联合维生素和FSH方案在成功实现自然妊娠方面分别优于其他方案。其他治疗方法对妊娠结局的疗效仍需要进一步验证。

Abstract

In this study, we used a network meta-analysis (NMA) to compare the effectiveness of medicines and supplements for idiopathic male infertility and to identify the best treatment. Medline, Excerpta Medica Database (EMBASE), Ovid, and China National Knowledge Infrastructure (CNKI), were searched for the period from January 1990 to June 2021 using the keywords ″male infertility,″ ″medical therapy,″ ″supplement/nutrient therapy,″ and related terms. Studies involving randomized controlled trials (RCTs) investigating medicines (mainly follicle-stimulating hormone (FSH), androgen, and clomiphene/tamoxifen) or supplements (mainly zinc, selenium, vitamin C or E, carnitine, coenzyme Q10 (CoQ10), or combined treatment) for idiopathic infertile men were selected for meta-analysis. Preferred reporting items for systematic reviews and meta-analysis (PRISMA) was used for data extraction, and a risk-of-bias tool and grades of recommendation, assessment, development, and evaluation (GRADE) system adapted to the NMA were employed to assess the quality of the evidence. The primary outcomes were live birth and spontaneous pregnancy rate (SPR). The secondary outcomes were sperm parameters (including concentration, progressive motility, and morphology) and side effects. In total, 65 RCTs involving 7541 men with sperm abnormalities but normal hormone levels were included. A total of 36 studies reported SPR but only three reported live birth rates. The quality of the included studies was found to be moderate to high. Compared with a placebo or being untreated, carnitine plus vitamins significantly improved SPR (relative risk (RR) = 3.7, 95% confidence interval (CI), 1.6–8.5); fatty acids significantly increased sperm concentrations (mean difference (MD) = 12.5 × 10⁶ mL^–1, 95%CI, 3.1 × 10⁶–22.0 × 10⁶); and selective estrogen receptor modulators (SERM) plus CoQ10 significantly improved sperm progressive motility (MD = 11.0%, 95%CI, 0.1%–21.9%) and normal sperm morphology (MD = 11.0%, 95%CI, 4.6%–17.4%). The most optimal intervention was carnitine plus vitamins and fatty acids for SPR and sperm concentrations, respectively, even after excluding trials at a high risk of bias. Compared with a placebo or being untreated, FSH (RR = 4.9, 95%CI, 1.1–21.3) significantly increased SPR, whereas SERM plus kallikrein increased sperm concentration (MD = 16.5 × 10⁶ mL^–1, 95%CI, 1.6 × 10⁶–31.4 × 10⁶), and SERM plus CoQ10 significantly improved sperm progressive motility (MD = 11.3%, 95%CI, 7.3%–15.4%) and normal morphology (MD = 11.2%, 95%CI, 5.4%–16.9%) in men with oligoasthenozoospermia (OA). In terms of side effects, fatty acids and pentoxifylline were associated with foul breath and/or a bad taste (RR = 8.1, 95%CI, 1.0–63.5) and vomiting (RR = 8.0, 95%CI, 1.0–63.0), respectively. In conclusion, the optimal treatment for male infertility for live birth is still unknown. Carnitine plus vitamins and FSH are likely to be better than other therapies in achieving successful spontaneous pregnancy in couples overall and in couples with men with OA, respectively. The efficacy of other treatments on pregnancy outcomes warrants further verification.

关键词

男性不育症 / 药物 / 补充剂 / 自然妊娠率 / 精子参数

Key words

Male infertility / Medicine / Supplement / Spontaneous pregnancy rate / Sperm parameters

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李建,吴奇,Ernest Hung Yu Ng,Ben Willem J. Mol,吴效科,Chi Chiu Wang. 一项关于药物和补充剂对改善男性不育症患者的自然妊娠和精液参数影响的系统综述和网状荟萃分析[J]. 工程（英文）, 2022, 16(9): 198-209 DOI:10.1016/j.eng.2021.07.009

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1、引言

高达50%的不育夫妇是由男性因素所导致的。不育症的男性病因包括先天或获得性泌尿生殖道异常、内分泌紊乱以及遗传和免疫因素。然而，大部分不育男性通过临床检查并不能确定病因，即所谓特发性不育[1]。除了不育症，多数特发性不育男性还常合并精子浓度低、活力差、形态异常或多种精子参数异常并存[2]。

药物和补充剂已被广泛用于治疗男性不育症[3]。这些药物主要属于激素或激素调节剂，它们通过下丘脑-垂体-睾丸轴来发挥作用，从而改善精子质量并最终使不孕夫妇成功妊娠。其中，促卵泡生成激素（FSH）和选择性雌激素受体调节剂（SERM，主要包括克罗米芬和他莫昔芬）经常被使用，尽管它们尚未获得美国食品和药物管理局（FDA）的批准[4]。一项荟萃分析显示：与安慰剂或未治疗相比，SERM显著增加自然妊娠率（SPR）以及精子浓度和前向活力精子[5]。目前，对于FSH治疗特发性男性不育的临床获益仍未明确。此外，关于治疗特发性男性不育的最佳方案尚不清楚，其有可能是FSH、SERM，但也可能存在其他疗法中。

除药物外，补充剂是另一种被广泛使用的治疗方案，包括维生素C/E、锌、硒以及卡尼汀等。这些补充剂的大部分都可充当抗氧化剂以保护精子免受活性氧类物质（ROS）所致的损伤[6]。比如卡尼汀，它是一种存在于附睾和精子中的季胺[7]，常常被用于治疗不育男性。一项荟萃分析表明，与安慰剂或维生素相比，左卡尼汀不仅显著改善精子质量，而且还显著增加SPR [8]。补充剂的另一机制则与线粒体的生化产能有关，它为精子的成熟和运动提供能量。例如，辅酶Q₁₀是线粒体呼吸链的组分之一，参与线粒体的产能[9]。既往研究表明，与安慰剂相比，辅酶Q₁₀显著提高精子浓度和活力[10‒11]，但其对生殖结局的疗效尚未得到验证，此外，关于药物联合补充剂是否比单用药物或补充剂具有更好的临床获益仍存在争议。

尽管已开展许多男性不育的临床试验，但因缺乏来自临床试验的某些药物疗效比较的直接证据，所以很难判定最佳的治疗方案。网状荟萃分析被设计为在一个统计模型中比较多种治疗方法[12‒14]，并通过严谨的方法学构建这些疗法的疗效等级，以指导临床实践[15‒16]。因此，在本研究中，我们进行了系统综述更新和网状荟萃分析，以比较不同药物和补充剂对特发性男性不育症的活产率、SPR和精液参数的疗效。

2、材料和方法

2.1 方案和注册

该研究的方案已在PROSPERO网站（CRD42020158348）注册†，并遵循适用于网状荟萃分析的系统评价和荟萃分析的优先报告项目（PRISMA）扩展声明[17]开展本研究。

2.2 文献检索

检索电子数据库包括Medline、EMBASE、Ovid和CNKI等自1990年1月至2021年6月公开发表的文献。本研究采用基于关键词的策略进行文献检索，检索文献为药物或补充剂治疗特发性男性不育症，并通过特定的过滤器进行临床研究刷选。过滤器则通过医学主题标题术语联合正文单词构建，使用的关键词包括：男性不育、少精症、弱精子症、少弱精子症（oligoasthenozoospermia, OA）、少弱畸形精子症（oligoasthenoteratozoospermia, OAT）、膳食疗法、微量元素、补充剂、卡尼汀、维生素、抗氧化剂、泛醌、氨基酸、脂肪酸、药物治疗、选择性雌激素受体调节剂（SERM）、芳香化酶抑制剂、雄激素、类固醇、促性腺激素和随机对照试验（附录A中的表1）。纳入分析文献无语言限制，但会议摘要被排除。

表1 对于不同研究结局的最佳干预方案

Outcomes	Pregnancy rate		Sperm concentration		Sperm motility		Sperm morphology
Outcomes	Intervention	RR (95% CI)	Intervention	MD (95% CI)	Intervention	MD (95% CI)	Intervention	MD (95% CI)
Overall	Carnitine + vitamin C/E [25‒27,30‒32,34‒35,37‒38,40,42‒44,46‒50,52,55,57,59‒60,63‒64, 66‒72,79,83]	3.7 (1.6, 8.5)	Fatty acid [27‒28,30‒31,33,37,39‒41,47,50‒52,54‒61,63,68,73‒77,80‒81,83‒84,86‒89]	12.5 × 10⁶ mL^‒1 (3.1, 22.0)	SERM + kallikrein [26‒27,30‒31,36‒37,39‒41,43,47,51‒56,59‒61,64,67‒68,70,72,74‒78,80‒81,84,87‒89]	13.0% (‒0.6%‒26.6%)	SERM + CoQ₁₀ [28,39,41,54,56‒57,59,61,63‒64,68‒69,74‒77,80,83‒84,87‒89]	11.0% (4.6%‒17.4%)
Sensitivity analysis
Excluded trials at high risk bias	Carnitine + vitamin C/E [25‒26,31,34‒35,37,40,42,44,46‒48,50,52,57,59,64‒68,70‒71,79,83]	5.1 (2.1, 12.6)	Fatty acid [28,31,33,37,39‒40,47,50-52,56‒57,59,68,73,75‒77,80,83‒84,86‒89]	12.5 × 10⁶ mL^‒1 (2.7, 22.3)	SERM + androgen [31,36‒37,39‒40,47,51‒53,56,59,64,67‒68,70,75‒77,80,83‒84,86‒89]	10.9% (‒1.0%‒22.8%)	Pentoxifylline [28,31,39,53,56‒57,59,64,68,74‒77,80,83‒84,87‒89]	8.5% (4.0%‒13.0%)
Excluded trials without AT	Carnitine + vitamin C/E [27,30,32,34‒36,38,42,44,46‒48,50,57,59‒60,64‒65,68‒70,72,83]	8.3 (0.9, 77.7)	GnRH [27,30,33,38‒39,41,47,50,54,56‒58,60‒61,68,73,75‒77,80,83‒84,86‒89]	15.3 × 10⁶ mL^‒1 (‒2.2, 32.9)	SERM + kallikrein [27,30,36,38‒39,41,47,54,56,59‒61,64,68,70,72,74‒76,80,83‒84,86‒89]	16.8% (4.3%‒29.4%)	Pentoxifylline [39,41,56‒57,59,61,64,68‒69,74‒77,80,83‒84,87‒89]	8.5% (6.4%‒10.6%)
Sensitivity analysis
OA	FSH [27,42‒44,46‒50,52,55,57,59‒60,63‒65]	4.9 (1.1, 21.3)	SERM + kallikrein [27,47,50‒52,54‒61,63]	16.5 × 10⁶ mL^‒1 (1.6, 31.4)	SERM + CoQ₁₀ [27,43,47,51‒54,56,59,61,64]	11.3% (7.3%‒15.4%)	SERM + CoQ₁₀ [53,56‒57,59,61,64]	11.2% (5.4%‒16.9%)

2.3 研究选择

只对已发表的RCT进行数据提取和分析，纳入RCT标准包括：①特发性不育男性伴精液异常，后者根据世界卫生组织（WHO）的标准确定[18]，包括畸形精子症（正常形态精子百分比小于4%）、少精子症（精子计数小于1.5×10⁷ mL^-1)、弱精子症（活动精子百分比小于40%）等其中一种，以及合并两种或以上的精液参数异常，但排除任何已知的损害精子发生或性激素异常等原因；②采用药物、补充剂或联合一种或多种手段对比安慰剂、无治疗以及其他治疗方案；③评价妊娠结局（包括自然生化/临床妊娠和活产）、精子参数（包括浓度、活力和正常形态）和（或）不良反应。研究的药物包括性激素[如重组/纯化的FSH、促性腺激素、雄激素（如睾酮及其衍生物）]、选择性雌激素受体调节剂（他莫昔芬和克罗米芬）、芳香化酶抑制剂（如来曲唑）或其他药物。补充剂包括微量元素（如锌、硒）、维生素（如维生素C、E、D₃和叶酸）、能量补充剂（如卡尼汀、辅酶Q₁₀、脂肪酸）或其他方案（如二羟睾酮和益生菌）。半随机对照试验或其他研究设计、重复发表试验以及受试者重叠的同一作者开展的研究等均被排除。由两位独立审阅者（J.L.和Q.W.）进行文献检索和研究筛选。任何分歧都经讨论且协商一致进行解决。

2.4 数据提取和结局

两位审阅者分别独立评估全文，并使用专门设计的表格从纳入的论文中提取数据，提取信息包括研究设计、试验地点、患者特征（纳入和排除标准）、样本量、治疗详细信息（干预方案、对照、治疗时间）、结局（活产、自然妊娠率和精子参数）和不良反应等。出现分歧则通过讨论或咨询第三位审阅者（C.C.W.）进行解决。

主要研究结局包括活产和自然妊娠（SPR）。活产被定义为妊娠28周后分娩一个有生机能儿。妊娠包括生化和临床妊娠，分别定义为血清人绒毛膜促性腺激素（hCG）试验阳性和经阴道超声检测到的具有胎心搏动的宫内妊娠。次要研究结局是精子参数（包括精子的浓度、前向运动比、形态）以及不良反应。

2.5 偏倚风险和证据质量评估

研究方法学的质量评估由两名独立审阅者采用Cochrane [19]偏倚风险工具进行。纳入的RCT被分为三类：低风险、高风险或风险不明确。采用适合网状荟萃分析的GRADE系统将研究证据分为四个级别：高、中、低和极低[20]。由于不同的比较可能具有不同的偏倚风险，通过网状贡献矩阵的数据可合理地解释每一块直接证据的相对贡献[20]。

2.6 数据合并和统计分析

我们开展一项网状荟萃分析，通过将直接和间接证据估计的相对疗效纳入单次分析中，以明确治疗方案上的任何差异，这可最小限度地减少偏倚。所有的网状荟萃分析都采用一个随机效应多元回归模型进行，并通过Stata软件中的“network”和“mvmeta”软件包实现（15.0版；Stata Corp LP，美国）[21‒22]。在进行网状荟萃分析之前，通过Stata软件包中适宜的局部和全局方法评价研究间的不一致性，并计算网状异质性和不一致性的I ² [21,23]。所有研究结局均未发现显著的异质性。由于缺乏相对效应的信息，所有干预措施的结局事件发生率为零或100%的研究均从分析中剔除。对仅单臂事件发生率为零的研究，给予每组均添加0.5效应进行校正。效应以95%的相对风险（RR）或加权均值差（MD）及其95%置信区间（CI）表示，以便于根据异质性的大小来解释结果。我们使用经对比校正的漏斗图来评估小样本研究效应，并通过累积排名曲线（SUCRA）下面积对所有治疗方案的累积排名进行统计汇总[21]。累积排名曲线是每一种干预相对于假定的治疗方案（通常情况下即为最好的治疗方案）的有效性百分比，累积排名曲线值越高，治疗方案疗效的似然比越高[24]。我们还根据偏倚风险、禁欲时间和精子异常的类型分别进行亚组分析和敏感性分析。统计分析和图形生成均采用Stata软件进行。偏倚风险的评估使用Cochrane综述管理工具（5.3版，Cochrane协作组织，丹麦）。所有统计学检验均为双侧，以p < 0.05为差异具有统计学意义。

3、结果

3.1 纳入研究特征

检索共获得6675篇文献。经筛选标题和摘要，293项研究被认为可能符合该综述的纳入标准，可通过获取全文进一步评估。最终共65项研究（7541名男性）被纳入本研究。文献选择过程的流程图如图1所示。

图1 PRISMA流程图。

纳入的研究在多个国家完成，除10项（15.4%）以中文发表，余均以英文发表。纳入研究的特征见附录A中的表S2。所有纳入的RCT均宣称受试者被诊断为特发性不育且无性激素异常。其中，10项研究为少精子症[25‒34]，7项研究为弱精子症[35‒41]，24项研究为少弱精子症[42‒65]，24项研究为两种以上类型异常精子参数[66‒89]。5项RCT没有提供基础激素水平，46项RCT报道了治疗前后经2~7天的禁欲时间才进行精液分析。所有的研究都评估精液参数，只有3项RCT报道活产率，36项RCT报道SPR。只有SPR和精子参数可进行网状荟萃分析。研究药物包括SERM（12项RCT，18.5%）、FSH（11项RCT，16.9%）、雄激素（4项RCT，6.0%）、己酮可可碱（3项RCT，4.6%）、促性腺激素释放激素（GnRH）（两项RCT，3.1%）和其他药物（每种药物各一项RCT，1.5%），包括人绒毛促性腺激素、激肽酶和吲哚美辛。补充剂包括卡尼汀（12项RCT，18.5%）、维生素C/E（7项RCT，10.8%）、辅酶Q₁₀（9项RCT，13.8%）、叶酸（两项RCT，3.1%）、乙酰半胱氨酸（两项RCT，3.1%）、锌（两项RCT，3.1%）和其他方案（每种补充剂各一项研究，1.5%），包括ω-3脂肪酸、硒、白藜芦醇和硫辛酸。药物联合补充剂包括SERM+维生素（4项RCT，6.2%）、卡尼汀+维生素（3项随机对照试验，4.6%）、选择性雌激素受体调节剂+雄激素（两项RCT，3.1%）、硒+维生素（两项RCT，3.1%），及其他（每种药物联合补充剂各一项RCT，1.5%），包括SERM+卡尼汀、SERM+辅酶Q₁₀、SERM+激肽酶、己酮可可碱+卡尼汀、硒+乙酰半胱氨酸。46项（70.8%）研究采用安慰剂对照，6项（9.2%）研究以未治疗作为对照；其余研究使用其他疗法作为对照。治疗时间通常为3~6个月。FSH剂量为75~300 IU，SERM为20~50 mg∙d^-1，肉碱为1~2 g∙d^-1，辅酶Q₁₀为30~200 mg∙d^-1，维生素C/E为200~400 mg∙d^-1。

3.2 研究质量评估

多数RCT的方法学质量被评为中等（70.8%）；有11个（16.9%）试验在随机序列产生偏倚中被评为高风险，12个（18.5%）试验在分配隐藏偏倚中被评为高风险。各项研究偏倚风险评估的详细情况见附录A中的图S1。根据GRADE分级系统（附录A中的表S2），各研究结局的证据质量多为中低等。根据偏倚风险评估工具，多数研究都存在方法学问题（比如，研究局限性）；质量等级的下调主要是由于研究的局限性、间接性和不精确性。

3.2.1. 妊娠率

在36项RCT（3439名男性）中，32项为双臂RCT，4项为四臂RCT。各干预措施的网状图如图2所示。网状荟萃分析表明，与安慰剂/未治疗相比，FSH (RR = 2.2, 95% CI 1.4~3.5)、人绒毛促性腺激素（RR = 2.6, 95% CI 1.5~4.5）、SREM (RR = 2.1, 95% CI 1.2~3.5)、卡尼汀（RR = 1.9, 95% CI 1.1~3.3）、卡尼汀联合维生素（RR = 3.7, 95% CI 1.6~8.5）、卡尼汀联合辅酶Q₁₀（RR = 3.3, 95% CI 1.6~6.8）、SERM联合雄激素（RR = 3.2, 95% CI 1.8~5.9）、SERM联合维生素（RR = 2.2, 95% CI 1.1~4.6）和SERM联合卡尼汀（RR = 2.3, 95% CI 1.2~4.3）均显著提高SPR。在排除高偏倚风险RCT或未报道精液分析禁欲时间的研究后，FSH、人绒毛促性腺激素、卡尼汀、SERM+雄激素和卡尼汀+辅酶Q₁₀仍具有统计显著性，而SERM、SERM+维生素和卡尼汀+维生素的统计显著性消失（图3）。在全部、排除高风险RCT以及排除未报道精液分析禁欲时间的RCT中，各干预措施对应的SUCRA值见图4。不管是否存在研究的风险偏移和精液分析禁欲时间，对于获得成功妊娠，最佳干预措施是卡尼汀联合维生素（表1 [25‒28,30‒44,46‒61,63‒81,83‒84,86‒89]）。漏斗图表明SPR不存在小样本研究效应（图5）。

图2 关于SPR的干预措施网状图。（a）整体干预措施网状图；（b）排除具有高偏倚风险试验后，干预措施网状图；（c）排除未报道精液分析禁欲时间试验后，干预措施网状图；（d）研究少弱精症的干预措施网状图。雄激素包括睾酮及其衍生物；SERM包括克罗米芬或他莫昔芬；Se为硒。

图3 与安慰剂或未治疗相比，各干预方案对SPR估算疗效的森林图。（a）与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的总体森林图；（b）排除高偏倚风险试验后，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的森林图；（c）排除未报道精液分析禁欲时间试验后，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的森林图；（d）对于研究少弱精子症的试验，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的森林图。

图4 与安慰剂或未治疗相比，各干预方案对SPR疗效的SUCRA。（a）与安慰剂或未治疗相比，各干预方案对妊娠疗效的总体SUCRA；（b）排除高偏倚风险试验后，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的SUCRA；（c）排除未报道精液分析禁欲时间试验后，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的SUCRA；（d）对于研究少弱精子症的试验，与安慰剂或未治疗相比，各干预方案对妊娠估算疗效的SUCRA。

图5 关于SPR的漏斗图。（a）估计报道偏倚和研究间异质性的总体漏斗图；（b）排除具有高偏倚风险试验后，估计报道偏倚和研究间异质性的漏斗图；（c）排除未报道精液分析禁欲时间试验后，估计报道偏倚和研究间异质性的漏斗图；（d）对于研究少弱精子症的试验，估计报道偏倚和研究间异质性的漏斗图。不同的颜色代表不同的比较。

3.2.2. 精子浓度

37项RCT（4084名男性）被纳入网状荟萃分析，32项为双臂RCT，三项为三臂RCT，两项为四臂RCT。各干预措施的网状图见附录中的图S2。与安慰剂或未治疗相比，促性腺激素释放激素（GnRH）（MD=6.1×10⁶ mL^-1, 95% CI 2.2×10⁶~9.9×10⁶）、SERM (MD=6.1×10⁶ mL^-1, 95% CI 0.4×10⁶~11.8×10⁶)、己酮可可碱（MD=10.0×10⁶ mL^-1, 95% CI 0.6×10⁶~19.5×10⁶）、脂肪酸（MD=12.5×10⁶ mL^-1, 95% CI 3.1×10⁶~22.0×10⁶）、SERM联合维生素C/E（MD=9.0×10⁶mL^-1, 95% CI 2.4×10⁶~15.6×10⁶）和SERM+辅酶Q₁₀（MD=10.6×10⁶mL^-1, 95% CI 1.5×10⁶~19.7×10⁶）均显著升高精子浓度。在排除高偏倚风险RCT或未报道精液分析禁欲时间的研究后，脂肪酸仍具有统计显著性（附录A中的图S3）。在全部、排除高风险RCT以及排除未报道精液分析禁欲时间的RCT中，各干预措施对应的SUCRA值见附录A中的图S4。不管是否存在研究的风险偏移，对于升高精子浓度，最佳干预措施是脂肪酸。漏斗图表明精子浓度存在中等程度的小样本研究效应（附录A中的图S5）。

3.2.3. 精子前向运动

38项研究（4290名男性）被纳入网状荟萃分析，34项为双臂RCT，两项为三臂RCT，两项为四臂RCT。各干预措施的网状图见附录A中的图S6。与安慰剂或未治疗相比，辅酶Q₁₀（MD = 7.4%, 95% CI 2.3%~12.4%）、卡尼汀（MD = 7.5%, 95% CI 2.1%~13.0%）、SERM联合辅酶Q₁₀（MD = 11.0%, 95% CI 0.1%~21.9%）和SERM联合雄激素（MD = 9.0%, 95% CI% 1.2%~16.8%）均显著升高精子前向运动百分比。在排除高偏倚风险RCT或未报道精液分析禁欲时间的研究后，只有辅酶Q₁₀在两者中均显著提高精子前向运动百分比（附录A中的图S7）。在全部、排除高风险RCT以及排除未报道精液分析禁欲时间的RCT中，各干预措施对应的SUCRA值见附录A中的图S8。即使排除未报道精液分析禁欲时间的研究，对升高精子前向运动百分比，最佳干预措施仍是SERM联合激肽酶。漏斗图显示精子前向运动存在中等程度的小样本研究效应（附录A中的图S9）。

3.2.4. 精子形态

24项研究（2718名男性）被纳入网状荟萃分析，20项为RCT，两项为三臂RCT，两项为四臂RCT。各干预措施的网状图见附录A中的图S10。与安慰剂或未治疗相比，己酮可可碱（MD = 8.5%, 95% CI 3.8%~13.2%）、辅酶Q₁₀（MD = 2.6%， 95% CI 0.1%~5.1%）、脂肪酸（MD = 5.3%, 95% CI 0.7%~9.9%）和SERM联合辅酶Q₁₀（MD = 11.0%, 95% CI 4.6%~17.4%）均显著增加正常精子形态百分比。在排除高偏倚风险RCT或未报告精液分析禁欲时间的研究后，己酮可可碱和脂肪酸仍具有统计显著性（附录A中的图S11）。在全部、排除高风险RCT以及排除未报道精液分析禁欲时间的RCT中，各干预措施对应的SUCRA值见附录A中的图S12。在全部RCT分析中，改善正常精子形态的最佳干预措施是SERM联合辅酶Q₁₀，但排除未报道精子分析禁欲时间的RCT后，最佳干预措施是己酮可可碱。漏斗图表明正常精子形态不存在小样本研究效应（附录A中的图S13）。

3.3 亚组分析

对具体的精子异常类型，由于仅有7项RCT研究少精子症和6项RCT研究弱精子症，这些数据未并合并分析。23项RCT研究少弱精子症可进行网状荟萃分析。与安慰剂或未治疗相比，FSH、SERM、卡尼汀联合辅酶Q₁₀显著提高SPR [图3（d）]。FSH、SERM联合辅酶Q10和SERM联合激肽酶显著升高精子浓度[附录A中的图S3（d）]。雄激素、辅酶Q₁₀、卡尼汀、SERM联合维生素C/E、SERM联合辅酶Q₁₀可显著提高精子前向运动百分比[附录中的图S7（d）]。仅SERM联合辅酶Q₁₀显著增加正常精子形态百分比[附录中的图S11（d）]。对精子浓度和前向运动的最佳干预措施分别为SERM联合激肽酶和SERM联合辅酶Q₁₀ [附录中的图S4（d）和图S8（d）]。

3.4 不良反应

36项研究（55.4%）未报道不良反应，22项试验（33.8%）报道未发生不良反应或严重不良事件，余下7项试验（10.8%）可用于定性分析。常见的副作用包括口臭/味觉下降（7.1%）、恶心和呕吐（6.4%）、腹泻（6.4%）、消化不良（5.6%）、烧心或食管反流（5.3%）、头痛（4.0%）、瘙痒（2.6%）以及头晕和眩晕（1.6%）。当服用脂肪酸和己酮可可碱时，分别显著增加口臭/味觉下降（RR = 8.1, 95% CI, 1.0~63.5）和呕吐（RR = 8.0, 95% CI, 1.0~63.0）的发生风险（表2 [42,66‒67,76‒77]）。

表2 不良事件

Adverse events		No. of study	Total No. of participants	Pairwise meta-analysis RR (95% CI)	p value
Foul breath or bad taste
	Fatty acids [77]	1	227	8.07 (1.03‒63.48)	0.047
Vomiting
	Pentoxifylline [76]	1	250	8.00 (1.02‒63.02)	0.048
Heartburn or reflux
	Fatty acids [77]	1	227	6.05 (0.74‒49.48)	0.093
Pruritis
	Fatty acids and kallikrein [67,77]	2	318	5.16 (0.61‒43.91)	0.133
Tremor
	Pentoxifylline [76]	1	250	5.00 (0.24‒103.10)	0.297
Seborrhea
	Kallikrein [67]	1	91	3.20 (0.13‒76.54)	0.473
Visual dysfunction
	Clomiphene [42]	1	141	3.04 (0.13‒73.43)	0.493
Burping
	Fatty acids [77]	1	227	3.03 (0.12‒73.51)	0.496
Constipation
	Fatty acids [77]	1	227	3.03 (0.32‒28.66)	0.334
Dyspepsia
	Pentoxifylline and clomiphene [42,76]	2	391	3.01 (0.73‒12.53)	0.129
Headache
	Pentoxifylline, androgen, and clomiphene [42,66,76]	3	443	2.64 (0.71‒9.81)	0.147
Diarrhea
	Pentoxifylline, fatty acids, and kallikrein [67,76-77]	3	568	2.25 (0.78‒6.46)	0.133
Nausea
	Pentoxifylline, fatty acids, and kallikrein [67,76-77]	3	568	2.12 (0.77‒5.81)	0.145
Dizziness or vertigo
	Pentoxifylline and clomiphene [42,76]	2	391	1.58 (0.42‒5.92)	0.501
Feeling tired
	Fatty acids and kallikrein [67,77]	2	318	1.04 (0.15‒7.38)	0.971

4、讨论

本研究就治疗特发性男性不育症的多种方法做了一个全面的概述。在单一合并分析中，对各治疗方案进行排序，以此确定改善特发性男性不育症的SPR和精液参数的最有效方案。但关于活产的研究非常有限，因此对该结局尚无法给出结论。此外，约半数试验未报道不良反应。不过，我们的研究表明：对所有夫妇，卡尼汀联合维生素在实现成功自然妊娠上方面要优于其他方案。FSH不仅显著改善精子质量，且显著提高SPR，尤其是对于少弱精子症男性。尽管，辅酶Q₁₀可显著改善精子活力，但其关于自然妊娠率疗效的证据有限。

无论是否存在激素缺乏[4]，在临床实践中，FSH和SERM被经验性地用于治疗特发性男性不育症已有几十年。既往的一项荟萃分析表明：与安慰剂相比，FSH可显著提高SPR，但该疗效并未在行辅助生殖技术（ART）的不孕夫妇中得到验证[10,90‒91]。另一项荟萃分析表明：FSH可显著升高精子浓度（MD 3.17×10⁶ mL^-1, 95% CI 2.44×10⁶~3.91×10⁶）[10]。然而，这种变化的临床意义有限，特别是对于重度少精子症，后者有着显著低的妊娠率[92]。在本研究中，我们证实FSH可显著增加精子浓度，并最终显著提高SPR。FSH在精子发生中所起的关键作用包括精原细胞增殖、代谢和细胞结构支持，以及向生殖细胞运输营养物质[93]。FSH对精子参数的疗效取决于治疗的剂量和时间[94]。FSH对精子参数的疗效已被证实存在剂量依赖效应，当FSH为低剂量（每周175~262.5 IU）时仅改善精子活力，而在高剂量（每周700~1050 IU）时，可增加精子浓度、总计数和前向活动[95]。另一方面，据报道，FSH给药时间大于4个月时精子参数获得显著改善[50]。因此，认为FSH对精子质量和SPR都有正面效应是合理的，但其最佳剂量和治疗时间尚不清楚，有待未来研究进一步验证。

尽管并没有获得FDA批准，SERM（主要包括克罗米芬和他莫昔芬）也被广泛用于治疗特发性男性不育症。它可单独应用或联合其他治疗方案，其通过抑制雌激素对下丘脑和垂体的正常负反馈而发挥作用，继而促进FSH和黄体生成素（LH）[96]的分泌。既往证据表明：与安慰剂或未治疗相比，克罗米芬或他莫昔芬不但显著升高精子浓度（MD = 5.24×10⁶ mL^-1, 95% CI 2.12×10⁶~88.37×10⁶）和前向运动百分比（MD = 4.55%, 95% CI 0.73%~8.37%），而且显著提高SPR（OR = 2.42, 95% CI 1.47~3.94）。此外，据报道，50 mg克罗米芬的疗效要优于25 mg [5]。然而，Cannarella等[97]的研究表明：与对照组[混杂有安慰剂、未治疗和（或）其他治疗方案]相比，SERM对精子浓度和活力的疗效有限，但可改善精子总数量、形态以及SPR。这些研究间的差异很可能与对照组有关。有趣的是，我们发现SERM联合辅酶Q₁₀可显著改善精子质量，尤其是对合并特发性少弱精子症的男性。已有研究证实：辅酶Q₁₀在精子的能量代谢和脂质氧化过程中均起重要作用[98]。补充辅酶Q₁₀不仅显著提高精子的抗氧化能力，且显著改善精子质量，如活力等，即不育男性的辅酶Q₁₀水平与精子活力存在正相关关系[37,99]。因此，SERM联合辅酶Q₁₀可显著改善精子质量是合理的。

尽管如此，我们的研究结果表明：卡尼汀联合维生素才是实现自然妊娠的最有效治疗方案。卡尼汀单独使用或联合其他治疗方案，如维生素，可显著改善精子质量和妊娠率已有相关报道。卡尼汀是一种水溶性抗氧化剂，主要从饮食中获取。它具有抗氧化应激效应，且可为精子提供能量[100‒101]。因此，卡尼汀也是治疗男性不育症最常用的抗氧化剂之一。目前，用于治疗男性不育症的维生素主要包括维生素C、维生素E和叶酸等。然而，维生素单独用于治疗男性不育症的直接证据非常有限，因此该治疗方案对妊娠的有效性在很大程度上是未知的[102‒103]。尽管一项荟萃分析显示：与安慰剂相比，使用维生素E可显著提高SPR，但该证据仅由一项研究数据合并，而该研究的方法学存在高偏倚风险，可能导致高估其疗效[104]。不过，维生素C或维生素E作为一种常用的抗氧化剂，常常与其他制剂（主要包括锌、硒、卡尼汀、辅酶Q₁₀或SERM）联合使用，这是治疗男性不育症非常常见的治疗方案。其中，一些研究结果表明：它们对精子参数、SPR或两者均有显著改善[105]。例如，与单独使用卡尼汀或维生素[38,79]相比，卡尼汀联合维生素可显著改善精子活力。然而，在本研究中，我们并未观察到维生素C或维生素E存在任何优于安慰剂的显著疗效。卡尼汀联合维生素被发现是实现成功自然妊娠的最有效方案，可能是基于其他未知的机制，如精子DNA碎片、精子去能或精液成分，其潜在机制有待进一步研究。

需要指出的是本研究存在几个局限性。第一，诸如精子参数等数据并非在所有纳入的研究中都有提供，从而导致用于精子参数分析的数据少于SPR。第二，由于研究数量有限，我们直接合并来自不同精子异常类型、药物的剂量/剂型以及治疗时限（如FSH）的数据，而不是将它们分成不同的类别，这可能会导致对一种干预措施的不精确疗效估计和排序，特别是连续型数据。第三，如草药和中药（TCM）等替代医学治疗方案未被纳入本研究。一般情况下，中医包括草药和针灸，而两者都可通过调节内分泌和抗氧化活性来改善精子参数和妊娠[106‒107]。然而，由于中医类研究通常存在研究质量偏低，中医成分尚未标准化或被充分描述等因素，从而难以将其纳入研究。最后，纳入该网状荟萃分析的大多数干预措施的都只有几个RCT，进而限制了各干预措施的网状连接性和统计功效。虽然排序分析提供了各干预措施对特定结局的更好概述，但它仅代表干预措施之间的相对排名而非绝对差异。因此，最佳治疗方案会因某一特定结局而有所不同[108]。

在未来的研究中，我们建议采用严格的方法学开展比较SERM（最好是50 mg克罗米芬）联合卡尼汀、辅酶Q₁₀或其他抗氧化剂的研究，以此验证SERM联合抗氧化剂对妊娠结局的疗效。抗氧化剂的剂量和治疗时限也应同时明确，特别是对于L-卡尼汀，因已有报道指出其在高剂量时具有毒性，比如50 mg∙mL^-1卡尼汀对精子有毒性，且显著降低精子活力[109]，此外，仅将生化或临床妊娠作为研究终点是不够的，最好是将结局评价延长至持续妊娠和活产[110]。同样，研究结局的报道应遵循CONSORT指南进行详细描述[111]，尤其是对于不良反应。尽管特发性男性不育症并不是单一的疾病，为了最大限度地增加所纳入研究的数量，这里仍然采用这个术语。在亚组分析中，研究结果表明：一种结局的总体最佳治疗方案与某种精子异常类型的结果有着较大的差异。因此，在诊断特发性男性不育症中，也必须明确具体的精子异常类型。

总之，关于改善男性不育症活产率的最佳治疗方案尚不清楚。对于所有的不孕夫妇或合并少弱精子症的男性，卡尼汀联合维生素和FSH在实现成功自然妊娠方面要优于其他治疗方案。其他治疗方案对妊娠结局的疗效仍需进一步验证，且应同时明确治疗的最佳剂量和时限。

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